Featured Research

In Alzheimer's disease, the problem is beta-amyloid, a protein that accumulates in the brain and causes nerve cells to weaken and die. Drugs designed to eliminate plaques made of beta-amyloid have a fatal problem: they need to enter the brain and remove the plaques without attacking healthy brain cells. New research, however, suggests that treatments modeled on the blockbuster cancer drug Gleevec could be the solution.

Share This

In Alzheimer’s disease, amyloid plaques (dark spots) are the hallmark of the disorder. When scientists knocked out the gene that produces GSAP in a mouse model of the disease (bottom), the mice developed fewer amyloid plaques.

In Alzheimer's disease, the problem is beta-amyloid, a protein that accumulates in the brain and causes nerve cells to weaken and die. Drugs designed to eliminate plaques made of beta-amyloid have a fatal problem: they need to enter the brain and remove the plaques without attacking healthy brain cells. New research from the laboratory of Nobel Prize winner Paul Greengard, however, suggests that treatments modeled on the blockbuster cancer drug Gleevec could be the solution.

Related Articles

Gleevec, it turns out, has the unique ability to bind to a protein that triggers the production of beta-amyloid plaques. The new research from Greengard's lab shows that this protein, called gamma-secretase activating protein (GSAP), dramatically and selectively increases the production of beta-amyloid peptide, which makes up the senile plaques found in the brains of most people with Alzheimer's. GSAP works through a mechanism involving its interactions with gamma-secretase, an enzyme that chops up the amyloid precursor protein, a large molecule produced naturally in the body and found in many different types of cells.

"Alzheimer's disease is a devastating disorder for which there are no satisfactory treatments," says Greengard, Vincent Astor Professor and director of the Fisher Center for Alzheimer's Research at Rockefeller. "Our findings reveal that gamma-secretase activating protein is a potential target for a new class of anti-amyloid therapies." Greengard won the 2000 Nobel Prize in Physiology or Medicine for research into how neurons communicate.

Scientists have been searching for ways to reduce beta-amyloid production in Alzheimer's patients by blocking gamma-secretase, but most gamma-secretase inhibitors also block the cleavage of an important immune system molecule called Notch. Notch plays a pivotal role in the development of blood-forming organs and the immune system. Earlier research by Greengard and his colleagues showed that Gleevec, a drug used to treat leukemia and gastrointestinal stromal tumors, successfully inhibited the ability of gamma secretase to form beta amyloid without affecting the Notch pathway.

In the new study, led by Gen He, a research associate in Greengard's lab, the researchers showed that GSAP stimulates production of beta-amyloid in cell lines, and that reducing GSAP reduces beta-amyloid. The researchers also looked at GSAP's action in a mouse model of Alzheimer's disease. They knocked down the gene that codes for GSAP using RNA interference, and found that levels of beta-amyloid as well as plaque development decreased. Biochemical studies showed that Gleevec reduces beta-amyloid production by binding to GSAP and preventing its activation of gamma-secretase.

Unfortunately, the Gleevec molecule does not cross the blood-brain barrier, the gatekeeper that prevents some substances in the blood from entering the brain. Greengard, however, believes that it will be possible to design drugs that target GSAP but do not have this limitation.

"Anti-amyloid therapeutic drugs represent a valid approach to treating Alzheimer's disease, but their inability to accumulate in the brain has limited their usefulness," says Greengard, who is head of the Laboratory of Molecular and Cellular Neuroscience. "The development of compounds that work like Gleevec, but have the ability to pass the blood-brain barrier and target GSAP could revolutionize the treatment of this disease."

This research was supported in part by grants from the National Institute of Aging, part of the federal government's National Institutes of Health, the U.S. Department of Defense, the Fisher Center for Alzheimer's Research Foundation and the F. M. Kirby Foundation. Additional funding was provided by Intracellular Therapies, Inc.

More From ScienceDaily

More Mind & Brain News

Featured Research

Mar. 31, 2015 — Memory and as well as connections between brain cells were restored in mice with a model of Alzheimer's given an experimental cancer drug, researchers report. "With this treatment, cells under ... full story

Mar. 31, 2015 — A criminologist finds that solitary confinement does not deter inmates from committing further violence in prison. The prisoners in the study who received solitary confinement were no more -- or less ... full story

Mar. 31, 2015 — Alcoholism takes a toll on every aspect of a person's life, including skin problems. Now, a new research report helps explain why this happens and what might be done to address it. "The clinical ... full story

Mar. 31, 2015 — Human language likely developed quite rapidly into a sophisticated system, a linguist contends. Instead of mumbles and grunts, people deployed syntax and structures resembling the ones we use today, ... full story

Mar. 31, 2015 — Coronary heart disease and stroke, two of the leading causes of death in the United States, are diseases associated with heightened platelet reactivity. A new study in humans suggests an underlying ... full story

Mar. 31, 2015 — A new study had researchers seeking answers to why the therapeutic benefit afforded by SSRIs was so limited in children and teenagers. If researchers can uncover the biological mechanisms preventing ... full story

Mar. 31, 2015 — New research reveals high-quality early education is especially advantageous for children when they start younger and continue longer. Not only does more high-quality early education significantly ... full story

Mar. 31, 2015 — During prenatal development, the brains of most animals, including humans, develop specifically male or female characteristics. But scientists have known little about the details of how this ... full story

Mar. 31, 2015 — A history of depression may put women at risk for developing diabetes during pregnancy, according to research. This study also pointed to how common depression is during pregnancy and the need for ... full story

Featured Videos

AAA: Distracted Driving a Serious Teen Problem

AP (Mar. 25, 2015) — While distracted driving is not a new problem for teens, new research from the AAA Foundation for Traffic Safety says it&apos;s much more serious than previously thought. (March 25)
Video provided by AP

Many Don't Know They Have Alzheimer's, But Their Doctors Do

Newsy (Mar. 24, 2015) — According to a new study by the Alzheimer&apos;s Association, more than half of those who have the degenerative brain disease aren&apos;t told by their doctors.
Video provided by Newsy

A Quick 45-Minute Nap Can Improve Your Memory

Newsy (Mar. 23, 2015) — Researchers found those who napped for 45 minutes to an hour before being tested on information recalled it five times better than those who didn&apos;t.
Video provided by Newsy

Related Stories

Oct. 3, 2013 — Autophagy, a key cellular auto-cleaning mechanism, mediates the formation of amyloid beta plaques, one of the hallmarks of Alzheimer's disease. It might be a potential drug target for the ... full story

July 1, 2013 — New research reveals that the likely culprit behind Alzheimer's has a different molecular structure than current drugs' target -- perhaps explaining why current medications produce little ... full story

Feb. 17, 2013 — Researchers have provided unequivocal evidence that under conditions which are approximately similar to those found in the brain, copper can only protect against beta amyloid forming beta sheets and ... full story

Sep. 1, 2011 — Alzheimer disease (AD) is the most common cause of dementia among older people. One of the main features of AD is the presence in the brain of abnormal clumps of the protein fragment beta-amyloid. ... full story

ScienceDaily features breaking news and videos about the latest discoveries in health, technology, the environment, and more -- from major news services and leading universities, scientific journals, and research organizations.